Furukawa Y, Lang A E, Trugman J M, Bird T D, Hunter A, Sadeh M, Tagawa T, St George-Hyslop P H, Guttman M, Morris L W, Hornykiewicz O, Shimadzu M, Kish S J
Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Neurology. 1998 Apr;50(4):1015-20. doi: 10.1212/wnl.50.4.1015.
We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.
我们评估了性别对遗传性进行性肌张力障碍/多巴反应性肌张力障碍（HPD/DRD）中GTP环化水解酶I（GCH）基因突变外显率的影响，并确定一些明显散发的HPD/DRD患者的疾病是否归因于GCH基因的新发突变。先前对HPD/DRD的临床研究表明，受影响的女性占多数，约一半的HPD/DRD患者为散发病例。我们对五个有至少两代受影响成员的HPD/DRD家族以及四个明显散发的病例及其所有父母进行了GCH基因的基因组DNA测序。在这九个HPD/DRD家系中，我们发现了GCH基因的独立突变（五个缺失、一个插入、一个无义突变和两个剪接受体位点的点突变）。HPD/DRD患者的女性与男性比例为4.3，GCH基因突变在女性中的外显率比男性高2.3倍（87%对38%，p = 0.026）。母系和父系遗传后代的外显率没有显著差异。所有四个散发病例都有新发突变，因为他们的父母都不是携带者。结果表明，HPD/DRD中GCH基因突变存在与性别相关的不完全外显率，并且这可能不是由于基因组印记所致。我们的数据还表明，在这种常染色体显性疾病中，GCH基因的自发突变率相对较高。
